1.
Regulatory gammadelta T cells induced by G-CSF participate in acute graft-versus-host disease regulation in G-CSF-mobilized allogeneic peripheral blood stem cell transplantation
Xuan, L., Wu, X., Qiu, D., Gao, L., Liu, H., Fan, Z., Huang, F., Jin, Z., Sun, J., Li, Y., et al
Journal of translational medicine. 2018;16(1):144
Abstract
BACKGROUND The immunomodulatory effects of granulocyte colony-stimulating factor (G-CSF) on T cells result in a low incidence of acute graft-versus-host disease (aGVHD) in G-CSF-mobilized allogeneic peripheral blood stem cell transplantation (G-PBSCT). However, the exact mechanism remains unclear. Regulatory gammadelta T cells (gammadeltaTregs), characterized by the presence of TCRgammadelta and Foxp3, have aroused great concern in the maintenance of immune tolerance. We hypothesized that gammadeltaTregs might involve in the immunomodulatory effects of G-CSF mobilization. METHODS The expression and immunomodulatory function of gammadeltaTreg subsets in peripheral blood of donors before and after G-CSF treatment in vivo and in vitro were evaluated by flow cytometry and CFSE assays. To investigate the effects of gammadeltaTregs on aGVHD, the association between gammadeltaTreg subsets in grafts and aGVHD in recipients was estimated. RESULTS The proportions of Vdelta1Tregs, CD27(+)Vdelta1Tregs and CD25(+)Vdelta1Tregs were significantly increased in peripheral blood after G-CSF treatment in vivo. gammadeltaTregs could be generated in vitro by stimulating with anti-TCRgammadelta in the presence of G-CSF. The immune phenotype, proliferation suppression function, and cytokine secretion of G-CSF-induced gammadeltaTregs were similar to that of transforming growth factor-beta (TGF-beta)-induced gammadeltaTregs. The clinical data demonstrated that the proportion of CD27(+)Vdelta1Tregs in grafts was significantly lower in the patients who experienced aGVHD than in those who did not develop aGVHD (P = 0.028), and the proportions of other gammadeltaTreg subsets in grafts did not differ significantly between the two groups. The best cutoff value for CD27(+)Vdelta1Treg proportion in grafts in prediction of aGVHD was 0.33%, with an area under the curve value of 0.725 (P = 0.043). Eight patients (26.7%) were classified as the low-CD27(+)Vdelta1Treg group (< 0.33%), and 22 patients (73.3%) as the high-CD27(+)Vdelta1Treg group (≥ 0.33%). The incidence of aGVHD was higher in the low-CD27(+)Vdelta1Treg group than in the high-CD27(+)Vdelta1Treg group (75.0% versus 22.7%, P = 0.028). CONCLUSIONS G-CSF could induce the generation of gammadeltaTregs in vivo and in vitro, and gammadeltaTregs might participate in aGVHD regulation in G-PBSCT.
2.
Granulocyte Colony-Stimulating Factor-Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease
Vasu, S., Geyer, S., Bingman, A., Auletta, J. J., Jaglowski, S., Elder, P., Donnell, L. O., Bradbury, H., Kitzler, R., Andritsos, L., et al
Biology of Blood & Marrow Transplantation. 2016;22(4):658-68
Abstract
We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late-activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 3.43). In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (>40 years) was associated with a higher incidence of relapse (P = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, whereas HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk. NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.